Syntheses of 4-[(1H,3H)-pyrimidine-2,4-dion-1-yl]- and 4-[(1H,3H)-5- methylpyrimidine-2,4-dion-1-yl]-1,6-heptadienes

Article abstract of DOI:10.1081/SCC-200051721

Heptadienes containing nucleic bases are attractive building blocks for the synthesis of carbocyclic oligonucleotide analogs. Herein, we report an alternative synthetic route to 4-[(1H,3H)-pyrimidine-2,4-dion-1-yl]-1,6- heptadiene and 4-[(1H,3H)-5-methylpyrimidine-2,4-dion-1-yl]-1,6-heptadiene via building the pyrimidine ring utilizing 4-isocyanato-1,6-heptadiene intermediate.

Full text of DOI:10.1081/SCC-200051721

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Syntheses of
4‐[(1H,3H)‐Pyrimidine‐2,4‐Dion‐1‐yl]‐ and
4
‐[(1H,3H)‐5‐Methylpyrimidine‐2,4‐Dion‐1‐yl]‐1,6
a
b
b
Kamal H. Bouhadir , Jing‐Lan Zhou & Philip B. Shevlin
a
Department of Chemistry , American University of Beirut , Beirut, Lebanon
Department of Chemistry , Auburn University , Auburn, Alabama, USA
b
Published online: 21 Aug 2006.
To cite this article: Kamal H. Bouhadir , Jing‐Lan Zhou & Philip B. Shevlin (2005) Syntheses of
4
‐[(1H,3H)‐Pyrimidine‐2,4‐Dion‐1‐yl]‐ and 4‐[(1H,3H)‐5‐Methylpyrimidine‐2,4‐Dion‐1‐yl]‐1,6‐Heptadienes,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
5:7, 1003-1010, DOI: 10.1081/SCC-200051721
3
To link to this article: http://dx.doi.org/10.1081/SCC-200051721
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Synthetic Communications , 35: 1003–1010, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200051721
Syntheses of 4-[(1H,3H)-
Pyrimidine-2,4-Dion-1-yl]- and
-[(1H,3H)-5-Methylpyrimidine-2,4-
Dion-1-yl]-1,6-Heptadienes
4
Kamal H. Bouhadir
Department of Chemistry, American University of Beirut,
Beirut, Lebanon
Jing-Lan Zhou and Philip B. Shevlin
Department of Chemistry, Auburn University, Auburn, Alabama, USA
Abstract: Heptadienes containing nucleic bases are attractive building blocks
for the synthesis of carbocyclic oligonucleotide analogs. Herein, we report an
alternative synthetic route to 4-[(1H,3H)-pyrimidine-2,4-dion-1-yl]-1,6-heptadiene
and 4-[(1H,3H)-5-methylpyrimidine-2,4-dion-1-yl]-1,6-heptadiene via building the
pyrimidine ring utilizing 4-isocyanato-1,6-heptadiene intermediate.
Keywords: Carbocyclic nucelosides, heptadiene, isocyanate, thymine, uracil
RESULTS AND DISCUSSION
Carbocyclic nucleosides have found increasing interest in a variety of
biomedical applications ranging from anti-HIV to antisense. We have
reported the synthesis of 1,6-heptadienes with pyrimidine bases attached
[
1]
utilizing the Mitsunobu reaction. We report herein an alternative synthetic
Received in the USA December 9, 2004
Address correspondence to Kamal H. Bouhadir, Department of Chemistry,
American University of Beirut, Box 11-0236, Beirut, Lebanon. Tel.: (961)-1-
350000, ext: 3984; Fax: (961)-1-365217; E-mail: kb05@aub.edu.lb

1
004
K. H. Bouhadir, J.-L. Zhou, and P. B. Shevlin
procedure of these molecules via constructing the pyrimidine ring using
-isocyanato-1,6-heptadiene 8. The synthesis of compound 8 started with
4
the malonic ester synthesis, where diethyl malonate 1 was added to a
solution of sodium ethoxide followed by allyl bromide to give diethyl allylma-
lonate 2. The same process was repeated to couple another molecule of allyl
bromide to yield diethyl diallylmalonate 3. Hydrolysis of compound 3 in an
alkaline solution gave diallylmalonic acid 4, which was decarboxylated
[2]
to give 2-(2-propenyl)-4-pentenoic acid 5. Refluxing compound 5 with
thionyl chloride formed the acid chloride intermediate 6, which was
allowed to react with sodium azide to give the acyl azide intermediate 7
that underwent the Curtius rearrangement to yield 4-isocyanato-1,6-
heptadiene 8 (Scheme 1).
The pyrimidine ring was constructed from 4-isocyanato-1,6-heptadiene
[3]
and the appropriate propanamide intermediate. The Reformatsky reaction
was utilized to react ethyl bromoacetate 9a with zinc metal followed by
triethyl orthoformate to yield ethyl 3,3-diethoxypropanoate 10a. Intermediate
1
0a was stirred with concentrated aqueous ammonium at room temperature to
[4]
afford the 3,3-diethoxypropanamide 11a. Sodium hydride was added to
compound 11a, followed by isocyanate 8, and the mixture was refluxed for
14 h to form 4-[(1H,3H)-pyrimidin-2,4-dion-1-yl]-1,6-heptadiene 12a.
Following a similar procedure, compound 12b was prepared, starting with
ethyl 2-bromopropanoate 9b. However, stirring 10b with concentrated
aqueous ammonia at room temperature did not form 11b. As a result, we
heated 10b in a sealed pressure vessel at 1008C for 20 h with concentrated
aqueous ammonia to obtain 3,3-diethoxy-2-methylpropanamide 11b. Addition
of 11b to a suspension of sodium hydride in dry THF gave the anion intermediate,
which was allowed to react with compound 5 and cyclize to form [(1H,3H)-5-
methylpyrimidin-2,4-dion-1-yl]-1,6-heptadiene 12b (Scheme 2).
Scheme 1.

Synthesis of Heptadienes
1005
Scheme 2.
EXPERIMENTAL
Melting points were determined on a MEL-TEMP apparatus in open capillary
tubes and are uncorrected. NMR spectra were determined in deuterated
solvents with TMS as the internal standard on a Bruker AM 250 NMR spec-
trometer. Chemical shifts are reported in ppm (d) downfield relative to TMS.
Infrared spectra were recorded as nujol mulls or KBr pellets using a Nicolet
SPC FTIR spectrometer with a Hewlett Packard ColorPro plotter. The IR
2
1
bands are reported in wavenumbers (cm ). Mass spectra were obtained
using either a Finnigan 3300 or a VG 7070E mass spectrometer. Reagents
and chemicals were purchased from the Aldrich Chemical Company
(Milwaukee, WI, USA), Sigma Chemicals, Fisher Scientific Company (Fair
Lawn, NJ, USA) and were used as received unless otherwise noted.
Diethyl Allylmalonate, 2
To a solution of sodium metal (48 g, 2.1 mol) in ethanol (1 L), diethyl
malonate (303.6 mL, 2 mol) was added dropwise under a steady stream of
nitrogen gas, during which the solution became white. Allyl bromide
(163 mL, 2 mol) was then added over 20 min and the mixture was refluxed
for 9 h. The solvent was evaporated under reduced pressure and the crude
product was distilled under reduced pressure to obtain the crude diethyl
1
allylmalonate (329 g, 82% yield, bp 73–758C at 11 Torr). H NMR
(
250 MHz, CDCl ) d 1.26 (t, 6H), 2.6 (t, 2H), 3.45 (m, 1H), 4.2 (q, 4 H), 5.2
3
1
m, 2H), 5.8 (m, 1H); C NMR (250 MHz, CDCl ) d 13.66 (q), 32.5 (t),
3
(
3
51.2 (d), 60.78 (t), 60.92 (t), 117 (t), 133.8 (d), 166.1 (s). Spectroscopic
data are consistent with those reported in the literature.
[5]
Diethyl Diallylmalonate, 3
To a solution of sodium metal (18.15 g, 0.79 mol) in dry ethanol (1 L), diethyl
allylmalonate (151.24 g, 0.76 mol) was added dropwise in a steady stream,

1
006
K. H. Bouhadir, J.-L. Zhou, and P. B. Shevlin
followed by the addition of allyl bromide (66.5 mL, 0.77 mol) over 40 min.
The mixture was refluxed for 17 h and the solvent was evaporated under
reduced pressure. The residue was washed with water (2 ꢀ 30 mL) and
dried by azeotropic distillation with benzene (40 mL). The crude diethyl
diallylmalonate was then distilled under reduced pressure to obtain the
crude diethyl diallyl malonate (159 g, 88.6% yield) that had a bp of 105–
[
6]
1
1
068C at 10 Torr (lit. bp 128–1308C at 12 Torr). H NMR (250 MHz,
CDCl ) d 1.20 (t, 6H), 2.59 (d, 4H), 4.12 (q, 4H), 5.06 (t, 4H), 5.59
(
3
1
m, 2H); C NMR (250 MHz, CDCl ) d 14.17 (q), 36.88 (t), 51.7 (s), 61.2
3
3
(
t), 119 (t), 132.5 (d), 170.6 (s).
Diallylmalonic Acid, 4
A mixture of diethyl diallylmalonate (146.6 g, 0.61 mol), potassium hydroxide
(
205.9 g, 3.7 mol), and water (206 mL) was refluxed with stirring for 12 h. The
cooled reaction mixture was extracted with diethyl ether (2 ꢀ 100 mL) to
remove any unreacted ester. The aqueous layer was acidified with concen-
trated hydrochloric acid (190 mL) and subsequently extracted with diethyl
ether (2 ꢀ 150 mL). The ethereal layer was dried over anhydrous MgSO
4
and filtered, and the solvent was evaporated under reduced pressure to give
an oily residue, which solidified upon cooling to yield white crystals (95 g,
[
6]
1
8
5% yield) that had mp 134–1368C (lit. mp 134–1358C). H NMR
13
250 MHz, CDCl ) d 2.59 (d, 4 H), 5.10 (m, 4 H), 5.60 (m, 2 H); C NMR
(
(
(
3
250 MHz, CDCl ) d 38.9 (t), 57.7 (d), 120.0 (t), 131.3 (d), 174.5 (s); MS
3
þ
EI), m/z (relative intensity) 166 (M , 6.82), 138 (12.87), 125 (100).
2-Allyl-4-pentenoic Acid, 5
Diallylmalonic acid (3.020 g, 0.0164 mol) was heated in an oil bath at 1508C
and the heating was stopped after the CO evolution ceased. The crude acid
was distilled under reduced pressure to form 2-allyl-4-pentenoic acid as a
2
[
7]
colorless liquid (2.10 g, 90% yield) that had bp 108–1108C at 1 Torr (lit.
1
bp 115–1208C at 3 Torr). H NMR (250 MHz, CDCl ) d 2.25 (m, 2H), 2.4
3
1
m, 2H), 2.57 (m, 1H), 5.05 (t, 4H), 5.71 (m, 2H); C NMR (250 MHz,
3
(
CDCl ) d 35.4 (t), 44.9 (d), 117.2 (t), 134.9 (d), 181.6 (s); MS (EI), m/z
3
þ
(
relative intensity) 140 (M , 3.01), 99 (82.1), 95 (100).
4
-Isocyanato-1,6-heptadiene, 8
A solution of thionyl chloride (42.8 g, 0.36 mol) and five drops of N,N-
dimethylformamide were stirred in a warm water bath and 2-allyl-4-
pentenoic acid (42 g, 0.3 mol) was added dropwise over 30 min. The mixture

Synthesis of Heptadienes
1007
was stirred for about 45 min in a warm-water bath to form the crude 2-allyl-4-
1
pentenoyl chloride 6 in a quantitative yield. H NMR (250 MHz, CDCl ) d 2.34
3
1
m, 2H), 2.47 (m, 2H), 2.95 (m, 1H), 5.08 (m, 4H), 5.7 (m, 2H); C NMR
3
(
(250 MHz, CDCl ) d 35.2 (t), 56.4 (d), 118.5 (t), 133.3 (d), 175.8 (s). The
3
crude 2-allyl-4-pentenoyl chloride was dissolved in methylene chloride
450 mL). A solution of tetrabutylammonium bromide (350 mg, 1.08 mmol)
(
and sodium azide (23.9 g, 0.367 mol) in distilled water (100 mL) was added
to the mixture and the flask was immersed in an ice-water bath. After stirring
for 3.5 h, the organic layer was separated and the aqueous layer was extracted
with CH Cl (2 ꢀ 25 mL). The organic layers were combined, anhydrous
2
2
magnesium sulfate was added, and the mixture stirred overnight at room temp-
erature until the evolution of nitrogen gas ceased. The solution was then filtered
and the solvent was evaporated under reduced pressure to yield the crude
product, which was purified by distillation (35.6 g, 86% yield from intermediate
1
5
(
, bp 64–658C at 9 Torr). H NMR (250 MHz, CDCl ) d 2.31 (m, 4H), 3.54
3
1
3
m, 1H), 5.16 (m, 4H), 5.78 (m, 2H); C NMR (250 MHz, CDCl ) d 40.7 (t),
3
5
4.8 (d), 118.8 (t), 133.6 (d); MS (EI), m/z (relative intensity) 96 (M-41,
6
reported in the literature.
4.7), 69 (71.3), 41 (100). Spectroscopic data are consistent with those
[
3]
Ethyl 3,3-Diethoxypropanoate, 10a
A mixture of zinc (42 g, 536 mmol), trimethylsilyl chloride (6 mL, 47 mmol),
and diethyl ether (1 L) was refluxed for 15 min, then cool down to room tempe-
rature. A solution of ethyl bromoacetate (55 mL, 496 mmol) and triethyl
orthoformate (87 mL, 523 mmol) was added dropwise over 20 min, and the
mixture was refluxed for 75 min then cooled down to room temperature.
The flask was immersed in an ice-water bath and a solution of aqueous hydro-
chloric acid (300 mL, 50% w/w) was added slowly with the evolution of
hydrogen gas. The organic layer was separated and the aqueous layer was
extracted with diethyl ether (3 ꢀ 100 mL). The ethereal layers were
combined and washed with aqueous sodium bicarbonate (5% w/w), dried
over anhydrous MgSO and filtered, and the solvent was evaporated under
4
reduced pressure to yield the crude ethyl 3,3-diethoxypropanoate (52 g, 55%
1
[4]
yield) with bp 86–898C at 9 Torr (lit. bp 848C at 12 Torr). H NMR
250 MHz, CDCl ) d 1.25 (m, 9H), 2.65 (d, 2H), 3.53 (q, 2H), 3.68 (q, 2H),
(
3
4
.17 (q, 2H), 4.97 (t, 1H).
Ethyl 3,3-Diethoxy-2-methylpropanoate, 10b
A mixture of zinc (45 g, 688 mmol), trimethylsilyl chloride (10 mL, 79 mmol),
and diethyl ether (1 L) was refluxed for 15 min and then allowed to cool down

1
008
K. H. Bouhadir, J.-L. Zhou, and P. B. Shevlin
to room temperature. A solution of ethyl-2-bromopropionate (70 mL,
39 mmol) and triethyl orthoformate (90 mL, 541 mmol) was added
5
dropwise over 40 min. The mixture was refluxed for 1 h and cooled down to
room temperature. The flask was immersed in an ice-water bath and glacial
acetic acid was added until the solution was clear. A solution of saturated
aqueous sodium bicarbonate was added until the formation of bubbles
seized. The solution was washed with saturated brine and the organic layer
was dried over anhydrous MgSO and filtered, the solvent was evaporated
4
under reduced pressure, and the crude product was distilled under reduced
[8]
pressure (66 g, 60% yield) with bp 87–898C at 9 Torr (lit. bp 95–988C at
1
6 Torr). H NMR (250 MHz, CDCl ) d 1.2 (m, 9H), 2.75 (p, 2H), 3.58
1
3
1
m, 4H), 4.12 (q, 2H), 4.62 (d, 1H). C NMR (250 MHz, CDCl ) d 12.688
3
(
3
(
q), 14.25 (q), 15.23 (q), 15.3 (q), 44.25 (d), 60.35 (t), 61.85 (t), 62.96 (t),
103.8 (d), 173.8 (s).
3,3-Diethoxypropanamide, 11a
A mixture of ethyl 3,3-diethoxypropanoate (50 mL, 231 mmol) and concen-
trated ammonium hydroxide (500 mL) was stirred at room temperature for
two days until the solution was clear. The mixture was extracted with chloro-
form (3 ꢀ 200 mL), the organic layers were combined, dried over anhydrous
MgSO , and filtered; and the solvent was evaporated under reduced pressure
4
to yield an oily residue that was triturated with cold heptane to produce white
crystals of 3,3-diethoxypropanamide (27.3 g, 73% yield) that had a mp
[
4]
1
5
0–528C (lit. mp 548C). H NMR (250 MHz, CDCl ) d 1.20 (t, 6H),
3
2.56 (d, 2H), 3.53 (q, 2H), 3.67 (q, 2H), 4.84 (t, 1H), 6.55 (br s, 1H), 6.70
(
br s, 1H); MS (Finnigan 3300, EI), m/z (rel intensity) 132 (M-29, 26.57),
116 (80.97), 103 (100), 88 (47.58).
3,3-Diethoxy-2-methylpropanamide, 11b
A 100-mL pressure vessel was charged with ethyl 3,3-diethoxy-2-
methylpropanoate (6.44 g, 31.5 mmol) and concentrated ammonium
hydroxide (40 mL). The flask was sealed and the mixture was stirred at
1208C for 24 h. The solution was cooled down to room temperature and
extracted with chloroform (3 ꢀ 50 mL). The chloroform layers were
combined, dried over anhydrous MgSO and filtered, and the solvent was
4
evaporated under reduced pressure to yield 3,3-diethoxy-2-methylpropanamide
as an oily material that was triturated with cold heptane to yield colorless
[8]
crystals (4.6 g, 42% yield), which had a mp of 63–658C (lit. mp 64.5–
1
6
68C). H NMR (250 MHz, CDCl ) d 1.20 (t, 6H), 2.56 (d, 2H), 3.53
3
(
q, 2H), 3.67 (q, 2H), 4.84 (t, 1H,), 6.55 (br s, 1H), 6.70 (br s, 1H).

Synthesis of Heptadienes
-[(1H,3H)-Pyrimidin-2,4-dion-1-yl]-1,6-heptadiene, 12a
1009
4
To a suspension of sodium hydride (5.13 g, 60% dispersion in paraffin oil,
29 mmol) and dry THF (50 mL) in an ice-water bath, a solution of 3,3-
1
diethoxypropanamide (5.64 g, 35 mmol) and dry THF (50 mL) was added
dropwise, during which the solution turned yellowish. When the evolution
of hydrogen gas ceased, a solution of 4-isocyanato-1,6-heptadiene (5.25 g,
3
8 mmol) in dry THF (50 mL) was added dropwise. The ice-water bath was
removed and the reaction mixture was refluxed under a nitrogen atmosphere
for 14 h. The reaction was quenched with water and the solution evaporated
under reduced pressure. The oily residue was suspended in diethyl ether
(50 mL) and water (50 mL). The organic layer was separated and the
aqueous layer was washed with diethyl ether (3 ꢀ 50 mL). The aqueous
layer was rendered acidic with concentrated hydrochloric acid and extracted
with diethyl ether (4 ꢀ 50 mL). The combined ether layers were dried over
anhydrous MgSO and filtered, and the solvent was evaporated under
4
reduced pressure to give the crude product. The product was crystallized
from acetone to yield colorless crystals (7.22 g, 61% yield, mp 92–948C).
1
H NMR (250 MHz, CDCl ) d 2.3–2.5 (m, 4H), 4.75 (p, 1H), 5.0–5.12
3
(
(
m, 4H), 5.6–5.75 (m, 2H), 5.72 (d, 1H), 7.12 (d, 1H), 7.79 (s, 1H), 8.35
1
s, 1H); C NMR (250 MHz, CDCl ) d 37.75 (t), 54.96 (d), 102.15 (d),
3
3
1
m/z (relative intensity) 206 (M , 5), 165 (76), 122 (100), 113 (13), 95
19.2 (t), 132.7 (d), 141.1 (d), 151.4 (s), 163.4 (s); MS (Finnigan 3300, EI),
þ
þ
(
41.5); HRMS (EI, M ) m/e calculated for C H N O 206.1055279;
1
1 14 2 2
found 206.105652.
4
-[(1H,3H)-5-Methyl-pyrimidin-2,4-dion-1-yl]-1,6-heptadiene, 12b
To a suspension of sodium hydride (2.7 g, 60% dispersion in paraffin oil,
7.5 mmol) and dry THF (50 mL) immersed in an ice-water bath, a solution
of 3,3-diethoxy-2-methylpropanamide (2.07 g, 11.8 mmol) and dry THF
25 mL) was added dropwise via an addition funnel, during which the
6
(
solution turned yellowish. When the evolution of hydrogen gas ceased, a
solution of 4-isocyanato-1,6-heptadiene (1.6 g, 11.6 mmol) in dry THF
(50 mL) was added dropwise. The ice-water bath was removed and the
reaction mixture was refluxed under a nitrogen atmosphere for 14 h. The
reaction was quenched with water and the solution was evaporated under
reduced pressure. The oily residue was suspended in diethyl ether (50 mL)
and water (50 mL). The organic layer was separated and the aqueous layer
was made acidic with concentrated hydrochloric acid and extracted with
diethyl ether (3 ꢀ 25 mL). The combined ethereal layers were dried over
anhydrous MgSO and filtered, and the solvent was evaporated under
4
reduced pressure to give an oily residue. The product was crystallized from

1
010
K. H. Bouhadir, J.-L. Zhou, and P. B. Shevlin
1
acetone to yield colorless crystals (1.17 g, 45% yield, mp 96–988C). H NMR
(
250 MHz, CDCl ) d 1.93 (s, 3H), 2.43 (m, 4H), 4.72 (m, 1H), 5.06 (m, 4H),
1
3
3
5
.7 (m, 2H), 6.92 (s, 1H), 9.3 (br s, 1H); C NMR (250 MHz, CDCl ) d 12.6
3
(
(
(
q), 37.8 (t), 54.7 (d), 110.6 (s), 118.9 (t), 133 (d), 136.6 (d), 151.5 (s), 163.7
þ
s); MS (Finnigan 3300, EI) m/z (relative intensity) 220 (M , 4.18), 179
þ
66.64), 136 (100), 127 (15.29), 109 (7.35). HRMS (EI, M ) m/e calculated
for C H N O 220.1212; found 220.1216.
12 16 2 2
ACKNOWLEDGMENTS
The authors are grateful to the Lebanese National Council for Scientific
Research (LNCSR) for partial financial support of this research project.
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